Implants with phased release of medicaments

ABSTRACT

The invention relates to implants with phasewise release of pharmaceutical substance, which consist of a core and layers arranged concentrically around it. The core and at least one of the layers contain different pharmaceutical substances or the same pharmaceutical substance in different doses. The pharmaceutical substance-containing areas consist of surface-eroding biodegradable polymer materials.

This application is a Rule 371 continuation of PCT InternationalApplication PCT/EP97/00820, filed on Feb. 20, 1997, which is acontinuation of German Application 196 08 423.7, filed on Mar. 5, 1996.

The invention relates to novel implants for the release ofpharmaceutical substance. These allow the same pharmaceutical substanceto be released in two or more phases or two or more pharmaceuticalsubstances to be released in a chronologically predetermined sequence.The implants consist of layers of biodegradable polymers which erodecompletely within a few weeks in the body.

Research in the field of controlled release of pharmaceutical substanceoriginally concentrated on releasing pharmaceutical substances at aconstant rate in order to achieve constant plasma or tissue levels.However, it was recognized that the discontinuous release ofpharmaceutical substances can also be very advantageous. By this means,for example, the development of tolerances can be prevented and inimmunization higher immune responses can be achieved. A further field ofapplication for pharmaceutical forms having discontinuous release istumour therapy. Tumour cells tend to develop resistances if the sameactive compound is administered continuously. Implants which releasepharmaceutical substances discontinuously or sequentially couldcounteract this development. An example of the potential use of suchimplants is the treatment of tumours in the area of the central nervoussystem. It is therefore desirable to have available locally implantablepharmaceutical release systems which make possible a phasewise releaseof different pharmaceutical substances or the same pharmaceuticalsubstance at different concentrations.

It has now been found that implants having a multilayer structure ofpharmaceutical substance-containing layers allow a phasewise release ofpharmaceutical substance if the pharmaceutical substance-containingareas of these implants consist of surface-eroding biodegradable polymermaterials.

The invention thus relates to implants with phasewise release ofpharmaceutical substance, which consist of a core and layers arrangedconcentrically around it, the core and at least one of the layerscomprising different pharmaceutical substances or the samepharmaceutical substance in different doses, which are characterized inthat the pharmaceutical substance-containing areas of the implantsconsist of surface-eroding biodegradable polymer materials.

The implants according to the invention consist of a core and one ormore layers of surface-eroding biodegradable polymer materials arrangedaround it concentrically, which can have different erosion rates.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the schematic structure of a two-layer implant incross-section. The core 1 is surrounded by a coating layer 2. Core 1 andcoating layer 2 consist of surface-eroding biodegradable polymermaterials and contain the respective pharmaceutical substance.

FIG. 2 shows the schematic structure of a four-layer implant incross-section. Here, a core 1 is surrounded by two intermediate layers 2and 3. A jacket layer 4 is arranged around them. Core 1 and jacket layer4 consist of surface-eroding biodegradable polymer materials and containthe respective pharmaceutical substance. The intermediate layers 2 and 3likewise consist of biodegradable polymer materials and are free ofpharmaceutical substance.

FIG. 3 shows the release from implants, in which firstCarboxyfluorescein and then Brilliant Blue are released.

FIG. 4 shows the release of Brilliant blue from implants having a core 1and layers 2, 3, and 4 as shown in Example 2.

In the simplest embodiment according to FIG. 1, the implant consists ofa pharmaceutical substance-containing core and a pharmaceuticalsubstance-containing coating layer. By appropriate choice of the polymermaterials, whose biodegradability in the body is surfaceerosion-controlled, it is guaranteed that the respective pharmaceuticalsubstance is released phasewise exclusively from the surfacecorresponding to the degradation of the polymer material. Thechronological duration and the release profile can be controlled byselection of the polymer materials according to differing degradability.Depending on the dimensioning of the coating layer and core and also thedose of the pharmaceutical substances embedded therein, their releasecan in each case take place strictly separately for days or weeks.

The pharmaceutical substance-containing areas of the implant can beloaded with different pharmaceutical substances. This is useful if acombination therapy with chronological graduation is demanded. Thepharmaceutical substance-containing areas of the implant, however, canalso contain one and the same pharmaceutical substance in differentdoses. By this means, optimum therapy is possible by means ofchronologically graduated, differing doses of pharmaceutical substance.

In a preferred embodiment, for example as shown in FIG. 2, between thepharmaceutical substance-containing areas 1 and 4 of the implant arearranged pharmaceutical substance-free intermediate layers 2 and 3. Thelatter likewise consist of biodegradable polymer materials. Preferably,these consist of bulk-eroding degradable polymer materials which areonly slowly degraded. By this means, an even stricter separation of thepharmaceutical substance release from the various pharmaceuticalsubstance-loaded areas of the implant can be effected.

The most diverse biodegradable polymer materials and their degradationproperties are known to the person skilled in the art. A selectionaccording to surface-eroding or bulk-eroding degradability is possiblewithout problems, if appropriate by using simple tests as a guide.

Compared with monolithic implants, the implants according to theinvention are distinguished by a greater flexibility in release. Thismakes possible the use of the implants in immunization and can preventdevelopment of tolerance in local tumour therapy.

The discontinuous release of a pharmaceutical substance and thesequential release of two or more pharmaceutical substances, as is oftenused, for example, in systemic chemotherapy is thus also possible intherapy using implants.

In spite of the higher complexing ability of the implants, these can beprepared using simple processes which allow mass production, such as,for example, compression, coating or extrusion. No disadvantages thusresult with respect to preparation.

The preparation of implants according to the invention can be carriedout, for example, as follows:

I. The polymers are first loaded with pharmaceutical substances for thepreparation of the pharmaceutical substance-carrying layers (layer 1 and2 or 1 and 4) shown in FIGS. 1 and 2. Two methods are suitable for this.

The corresponding polymers are fused and the pharmaceutical substancesare dissolved or suspended in the melt. After solidification, the solidpharmaceutical substance-loaded polymer is obtained. This method issuitable, for example, for all heat-stable pharmaceutical substances.

The polymers are dissolved in an organic solvent. The pharmaceuticalsubstance is dissolved or suspended in this mixture. By evaporating thesolvent, a solid polymer/pharmaceutical substance mixture is obtained.

II. In a second step, the pharmaceutical substance-containing polymersare ground to give a flowable powder for the preparation of rapidlyeroding layers (layer 1, 2 in FIG. 1 or 1 and 4 in FIG. 2).

III. The core 1 of the implant (see FIGS. 1 and 2) is prepared bycompressing the pharmaceutical substance-containing polymer powder. Ahydraulic press or a tablet press, for example, is suitable for thispurpose.

IV. The preparation of a two-layer implant (see FIG. 1) is carried outlike the preparation of laminated tablets.

V. The pharmaceutical substance-free intermediate layers 2 and 3 formultilayer implants (see FIG. 2) are prepared by compressingpharmaceutical substance-free polymer granules. To do this, for example,a base disc is first pre-pressed, on which is centered the core 1. Anappropriate amount of polymer granules is heaped over it and thencompressed. The application of the third layer can also be carried outby repeated immersion in a 20% polymer solution. The material used is abulk-eroding polymer. The article is then dried for 48 hours. Finally,pressing-on of a pharmaceutical substance-loaded jacket 4 is carried outanalogously to step IV.

The following examples show the release profile of low molecular weightsubstances from a four-layer implant. The model substances used areBrilliant Blue and Carboxyfluorescein. Investigation of the release wascarried out at 37° C. in 10 ml of 0.1 M of phosphate buffer solution, pH7.4. The content determination was carried out photometrically.

Instead of these model substances, any desired pharmaceutical substancescan be employed for the release investigations.

EXAMPLE 1

Implants with sequential release of two different low-molecular weightsubstances:

Materials Used:

    ______________________________________                                        Layer  Polymer      Colourant     Loading (%)                                 ______________________________________                                        Core 1 p(CCP-SA)20:8*                                                                             Brilliant Blue                                                                              30                                          Layer 2                                                                              p(CPP-SA)20:8*                                                                             --            --                                          Layer 3                                                                              poly(D,L-lactide)                                                                          --            --                                          Layer 4                                                                              p(CPP-SA)20:8*                                                                             Carboxyfluorescein                                                                          5                                           ______________________________________                                         *poly[1,3 bis (pcarboxyphenoxy)propane-co-sebacic acid].20:80 [sic       

Geometric Dimensions and Weight:

    ______________________________________                                        Implant  Height [mm]   .o slashed. [mm]                                                                      Weight [mg]                                    ______________________________________                                        Core 1   0.95 ± 0.05                                                                              4       14.0 ± 0.5                                  Layer 2  1.74 ± 0.03                                                                              6       56.4 ± 1.1                                  Layer 3  1.90 ± 0.07                                                                              n.d.**  64.8 ± 1.5                                  Layer 4  3.52 ± 0.04                                                                              8       202.2 ± 2.3                                 ______________________________________                                         **not determined                                                         

FIG. 3 shows the release from implants, in which firstCarboxyfluorescein and then Brilliant Blue are released. The release ofBrilliant Blue during the first 10 days is largely suppressed and onlycommences to an increased extent after this time.

EXAMPLE 2

Implants with sequential release of the same substance

Materials Used:

    ______________________________________                                        Layer    Polymer      Colourant  Loading (%)                                  ______________________________________                                        Core 1   p(CCP-SA)20:8*                                                                             Brilliant Blue                                                                           60                                           Layer 2  p(CPP-SA)20:8*                                                                             --         --                                           Layer 3  poly(D,L-lactide)                                                                          --         --                                           Layer 4  p(CPP-SA)20:8*                                                                             Brilliant Blue                                                                            5                                           ______________________________________                                         *poly[1,3 bis(pcarboxyphenoxy)propane-co-sebacic acid].20:80 [sic        

Geometric Dimensions and Weight:

    ______________________________________                                        Implant  Height [mm]   .o slashed. [mm]                                                                      Weight [mg]                                    ______________________________________                                        Core 1   0.89 ± 0.03                                                                              4       14.6 ± 0.5                                  Layer 2  2.55 ± 0.06                                                                              6       89.4 ± 2.8                                  Layer 3  2.92 ± 0.07                                                                              n.d.**  103.9 ± 3.9                                 Layer 4  4.50 ± 0.09                                                                              8       268.4 ± 2.9                                 ______________________________________                                         **not determined                                                         

FIG. 4 shows the release of Brilliant Blue from such systems. In thefirst and second phases, in each case 50% Brilliant Blue is released.

What is claimed is:
 1. An implant for phase-wise release ofpharmaceutical agents, comprising:a core and a plurality of layersarranged concentrically around said core, wherein the core and at leastone of said layers comprise different pharmaceutical agents, or the samepharmaceutical agent in difference doses, wherein thepharmaceutical-comprising areas of the implant comprise asurface-eroding biodegradable polymer, and wherein there is at least onepharmaceutical agent-free layer comprising a biodegradable polymerbetween at least two said layers comprising a pharmaceutical agent. 2.An implant of claim 1, wherein the core and at least one layer comprisedifferent pharmaceutical agents.
 3. An implant of claim 1, wherein thecore and at least one layer comprise different doses of the samepharmaceutical agent.
 4. An implant of claim 1, wherein thepharmaceutical agent-free layer comprises a bulk-eroding polymer.
 5. Animplant of claim 1, wherein there are two pharmaceutical agent-freelayers comprising a biodegradable polymer between two said layerscomprising a pharmaceutical agent.